Stroke is the leading cause of severe long-term disability in adults in the United States. Unfortunately, there are no clinical approaches proven to promote functional improvement once stroke has occurred. Recent studies using animal stroke models have demonstrated that treatment with an anti-Nogo-A antibody (Ab) improved motor functional recovery and enhanced the adult brain to rewire, i.e. enhanced Neuroplasticity. Further understanding of the dynamics underlying such improvement and brain reorganization is in great need. In this study we propose to use the small-animal micro positron emission tomography (5PET) and micro computed tomography (5CT) to provide in vivo 3-dimensional (3D) imaging and investigate the correlations between brain activity, functional improvement, and neuroanatomical plasticity in the rat following stroke and anti-Nogo-A Ab treatment. In vivo 3D PET imaging provides the opportunity of direct observation of the correlations between the responses of a biological system in response to treatment, challenge, and manipulations. It also enables longitudinal studies and significantly improves data quality by eliminating inter-animal variability while providing increased observation points. Since animals will not be sacrificed at regular intervals for histological analysis, the total number of animals needed is greatly reduced. In this proposal, we will first develop a novel model using 5PET/5CT imaging to detect brain activity of rats corresponding to a specific motor activity, the skilled forelimb reaching task. We will further combine this in vivo 5PET/5CT imaging method with our well-established and reproducible model for stroke, and recovery, and neuroplasticity. We will use this novel approach to examine whether 5PET/5CT imaging can detect changes in motor activity of the unlesioned hemisphere corresponding to the functional recovery after stroke and anti-Nogo-A Ab treatment in adult rats. Results derived from this proposed study will provide in depth information of understanding brain activity in areas such as the sensorimotor cortex and striatum, during the progression of motor functional improvement and corresponding brain reorganization after stroke and anti-Nogo-A Ab treatment. Such information will be of great value in future development of new approaches to enhance functional improvement, and benefit patients suffering from the sequelae after stroke.